Preparation of 2-octalones



, 9, 1966 J. H. BLUMENTHAL 3,265,739

' PREPARATION OF 2-OCTALONES Filed Feb. 23, 1962 3 Sheets-Sheet 1INVENTOR. Jqc/rHBLuMsA/mAL MAJWM 9, 1966 r J. H. BLUMENTHAL 3,265,739

I PREPARATION OF 2-OCTALONES 3 Sheets-Sheet 2 INVENTOR. J cIrH B1. UMEN17mg BY HTTDP/VE/OT mm N.

ue v 892 Qua: 23m

aqua 83 MEOR F'ilea Feb. 23. 19 2 g- 1966 J. H. BLUMENTHAL 3,265,739

PREPARATION OF Z-OCTALONES Filea Feb. 23, 1962 3 Sheets-Sheet 5 TONEfii-T MVELENGI'H (MC/Poms) a INVENTOR. o q & Q Q o h zffilC/(HBLUMENN/AL0 d o o A BY samusaosay perfumes; also to intermediates therefor.

United States Patent Office Patented August 9, 1966 3,265,739PREPARATION OF Z-OCTALONES Jack H. Blumenthal, New Monmouth, NJ.,assignor to International Flavors & Fragrances Inc., New York, 5 N.Y., acorporation of New York Filed Feb. 23, 1962, Ser. No..175,028

' 4 Claims. (Cl. 260--586) This invention relates to unsautratedbicyclic ketones and the corresponding saturated compounds which areThese unsaturated ketones belong in the family of compounds known as2-octalones.

The principal object of the invention is to provide a series of usefulcompounds of the type mentioned, and to provide simple, etiicientprocesses for the production of such compounds.

The invention comprises the novel products and processes the specificembodiments of which are described hereinafter by way of example, and inaccordance with which I now prefer to .practice the invention.

I have found in accordance with my invention compounds having theformulae and CH: CH:

where R is H or a lower alkyl containing not more than 4 carbon atoms.More specifically, I have found two tetramethyl substituted unsaturatedbicyclic ketones I and II, and the ketone obtained by hydrogenation ofthe double bond thereof, III: s

The above compounds, except the intermediate alcohol IV, possess odorswhich are useful as perfume materials.

I have found in accordance with my invention that ketones such as I orII may be prepared by the process which comprises cyclizing the compoundi cm R where R is either H or a lower alkyl containing not more than 4carbon atoms, with a strong mineral acid selected from the groupconsisting of concentrated sulfuric acid and polyphosphoric acid toproduce a substance selected from the group consisting of CH3 CH3 and CHCH3 where R is as above.

The unsaturated ketones I and II, where R is CH; are synthesized by thecyclization of geranyl isobutyronitrile CH; CH!

CH ll ll.

CH; CH;

with phosphoric acid and then cyclization of VI with either concentratedsulfuric acid or polyphosphoric acid to form the bicyclic ketones I orII. Another method of obtaining ketone II is by the isomerization of Iwith a dilute solution of hydrogen chloride in methanol or with a dilutesolution of sodium methylate in methanol.

The carbon-carbon double bond of ketone II is readily hydrogenated atroom temperature with 5% palladium on carbon as catalyst, withoutaffecting the carbonyl group, to give a practically quantitative yieldof III. The carbon-carbon double bond of I is difficult to hydrogenateat 240 mu.

v 3 without, simultaneously reducing the carbonyl 1 group. However, asan alternative procedure I may be completely reduced to the saturatedalcohol IV which then may be reoxidized under standard conditions to thesaturated ketone. and VIII and the corresponding saturated ketone IX(disclosed below) may be similarly prepared by the above proceduresstarting with geranyl propionitrile (X) [prepared in accordance with mycopending applicationSerial No. 112,916], in place of ger'anylisobutyronitrile, The formulae are as follows:

The process by which the ketones herein described are prepared includes(a) the novel preparation of 2'-octalones from a nitrile, and (b) thenovel formation of such bicyclic structure in one step from an aliphaticcompound. The mechanism of this reaction for ketones I and II,

passing through V and VI is believed to proceed as indicated below viathe monocyclic nitrile:

CH3 CH3 CH; CH

Carbonlum compound from VI I+II, and also traces of the materialindicated above where the dotted double bond to the left of the dottedvertical double bond appears The infrared spectrum of ketone I showsstrong absorptions Which are indicative of a non-conjugated carbonyl(1720 cm.- and gem-dimethyl groups (1362 and 1385, ems- The infraredspectrum of ketone 11 shows strong absorptions indicative of aconjugated carbonyl (1672 and 1625- cm.- and gem-dimethyl groups (1365and 1382 cm. and also a strong absorption at 880 cm.--. Ketone II alsoexhibits a typical .UV absorption ture of I, II and III as represented.

. Thetemperature of reaction for I may vary from '---20 to +20", while-10 to is preferred. .At higher temperatures increasing amounts of theconjugated. isomer are produced while cooling below is not economicalThe trimethyl substituted octalones VII on a large scales Any organicsolvent which will not react with concentrated sulfuric acid orpolyphosphoric acid at reaction temperature may be use-d. Nitropropaneandsaturated hydrocarbons such as hexane are good solvents for thisreaction. The usual commercial grade of concentrated sulfuric acid (96%)is preferred because of its convenience, although concentrations as lowas NMRabsorption curves confirm the strucof the isomeric ketones.

% have given equally good results. The ratio of moles of concentratedsulfuric acid per mole of nitrile is not critical and has been variedfrom l(sulfuric):l(nitrile) to 20:1 with good results. For theconjugated isomer, a commercial grade of polypho'sphoric acid hasbeenused, although other preparations of varying percentages of P 0 mayprove equally useful.

The following are examples of the process as I now prefer to practiceit. It is to be understood that the invention is not to be considered aslimited to the examples except as indicated in the appended claims.

All temperatures mentioned herein are in C.

All pressures herein are in mm. of mercury unless otherwise indicated.

EXAMPLE 1 To a mixture of 420 grams of concentrated sulfuric acid (96%)and 500 ml. of hexane which had been cooled to --l0 was added with goodstirring a pre-cooled solution of 168 grams (0.82 mole) of geranylisobutyronitrile prepared as above described, in an equal volume ofhexane over a period of 20 minutes, while maintaining the temperature ofthe reaction at --10.; The cooling bath was removed and the mixturestirred until the temperature reached 0- (about 10 minutes). Thereaction mixture was then poured with stirring into a mixture of 800grams of ice and 800 grams of water. The mixture was adjusted withsodium hydroxide to pH 5 while maintaining the temperature under 30. Itcontained an oil and an aqueous layer. The oil layer was separated andthe aqueous layer, after standing for 30 minutes was extracted twicewith hexane. The combined organic layers were washed twice with 10% H80; and then washed mm. through a 12 packed column gave a goodseparation The main fraction was ketone I; boiling point at 2 mm. n1.4930.

NMR (Nuclear Magnetic Resonance) absorption data confirmed thestructures of the ketone as follows:

The infrared curve referred to below shows the presence ofnon-conjugated ketone I and a trace of ketone II. The product has afine, woody perfume.

Geranyl isobutyronitrile may be prepared by the condensation ofisobutyronitrile with the allylic chloride obtained by the addition ofHCl to myrcene (US. Patent 2,882,323) by means of sodamide, as describedin my copending application Serial No. 112,916.

EXAMPLE 2 To 2400 grams of polyphosphoric acid at 50 was added withstirring in about one hour, 4l0 grams (2 moles) of geranylisobutyronitrile. The temperature was allowed to rise during theaddition to 105. The reaction mixture was stirred for two hours at -105and then was poured with stirring into 7200 grams of warm water. The

mixture was adjusted to a pH of 5 by addition of 30% sodium hydroxideand then stirred at 70-.-80 for one hour. Two layers formed. The lowerlayer was separated and the upper layer washed twice with 300 grams ofaqueous HCl (1:1); then succesively with salt solution, 5% sodiumcarbonate and salt solution. The solvent was distilled oif and theresidue flash distilled at 3 mm. The

mm. The main out which solidified on standing weighed 1 distillate wasfractionated through a 12 plate column at 3 257 grams-and tested 97%ketone (60% of theory). Re-

crystallization from aqueous ethanol yielded ketone II,

a white crystalline solid, meltingat 58, which showed 1 one peak by VPC.Its UV absorption was that expected of a conjugated ketone of this typewith ax max of 240nm, 15,900. The product has a woody, tobacco likeperfume.

' NMR absorption data confirmed the structure of the ketone as follows;

Tau value: Multiplicity 9.23, 9.05 Doublet. 9.01 p v 'Singlet. 8.55,8.45, 8.36 Multiplet. 8.00, 7.85 .DO.

' Singlet.

, residue (25 grams) was fractionated at 3- mm. through a short column.The distillate had not absorption at 240 m showed only one peak at VPCand had the following physical constants: B.P.. 105/ 3 mm., n 1.4827, D0.9512. On standing the material formed white crystals.

melted at 35. The product has a sweet, woody perfume.

NMR absorption data confirmed the structure of the ketone as follows:

' t Multiplicity Tau value: v

9.17, 9.03 Doublet. 9.00, 8;.86 Do.

8.63 Multiplet. 2

Do. EXAMPLE 4 To a mixture of 58 grams of concentrated sulfuric acid and70 ml. of hexane which was cooled to --10' was added with stirring acooled solutionof 22 grams of geranyl propionitrile in 22 ml. of hexaneover a period of fifteen minutes. The temperature was maintained at'-10' during the addition by cooling with a Dry Ice acetone bath. Afterthe addition was, completed, the cooling bath was removed and thestirring continued for fifteen I minutes while the temperature rose to0. The reaction mixture was then poured with stirring .into a mixtureof110 grams of ice and 110 grams of water and the aqueous mixture broughtto a pH of 7 with 20% sodium hydroxide solution. Two layers formed. Theupper layer was separated and the aqueous lower layer extracted oncewith 100ml. of. benzene. The combined organic layers were tion, 5%sodium bicarbonate and salt solution and dried over magnesium sulfate.The solvents werestripped off and the residue distilled. The distillate(B.P. 86' at 0.7 mm.) contained 90% ketone (m.w. 192) by oximation,

' and showed one major and two minor peaksby V.P.C.

Infra red absorption indicated thatthe product contained ketone VH andsome ketone VIII. rich, attractive, .woody perfume. I

Geranyl propionitrile was prepared by the condensation of propionitrilewith the-allylic chloride obtained by I the addition of BC! to myrcene(aecordin'gtoU.S. Patent After recrystallization from aqueous ethanolketone III enemas No. 2,882,323) byrneans EXAMPLE 5 Part A In a threeliter stainless steel autoclave was placed 248 grams of crude ketone I(obtained as in Example 2-before fractionation), 260 grams of diisobutylcarbinol and The mixture was hydrogenated at 200 and 2000# hydrogenpressure p.s.i. un-

60 grams of Raney nickel.

til absorption of gas ceased. After cooling to 50 the catalyst wasremoved, the solvent stripped off under vacuum and the residue distilledat 3 mm. through a short column filled with Berl saddles. There wasobtained, 224 grams of the saturated alcohol IV, B.P. 110- 120 'at 3mm., which crystallized on'standing.

Part B Y withbrine, 10% sodium carbonate solution and brine again untilneutral to litmus. The solvent was distilled off and the residuedistilled rapidly through a short col-v umn at 3 mm. The distillate wasfractionated through a 10 plate column to yield 178 grams of ketone III,B.P.

as -100 at 2.5 11;, 1.4827, or: 0.950s.

' EXAMPLE 6 In a one liter flask was placed 237 grams of methanol and11.5 grams of hydrogen chloride was added. With v washed twice with 10%sulfuric. acid, then with salt solu- 6 The product had a Mining, 237grams of crude ketone I (obtained as in Example 2-before fractionation)was added. The solution was refluxed for two hours and then poured intoa mixture of 950 grams of water and 220 grams of benzene. After stirringfor ten minutes, the aqueous layer was separated and the upper layer waswashed with 10%- sodium carbon-ate and then with water until neutral tolitmus. tilledrapidly through a short column at 3 mm. The distillate wasfractionated through a 12 plate column and yielded grams of materialwith a congealiu'g point of 40 or higher. This material contained about3% of ketone I by V.P.C. On recrystallization from dilute ethanol pureketone II was obtained.

In the accompanying drawings forming part of this application:

FIGURE '1 is an infrared graph for ketone'I.

FIGURE 2 is an infrared graph for ketone II.

FIGURE 3 is an infrared graph for ketone III.

I claim: 1

1 The process which comprises cyclizing the compound where R is selectedfrom thegroup consisting of H and lected from'the group consisting ofconcentrated sulfuric of sodamide, as described in my copendingapplication Serial No. 112,916.,

The solvent was removed and the residue dis- 7 acid and apolyphosp'horic acid to produce a cyclizcd substance selected from thegroup consisting of CH, CH.

OH; R

and

where R is as above.

2. The process which comprises cyclizing geranyl isobutyronitrile bysubjecting it to concentrated sulfuric acid to produce3,3,5,5-tetramethyl-A P-octalone-2, having 3. The process whichcomprises cyclizing geranyl isobutyronitrile by subjecting said nitrileto polyphosphoric 8 acid to produce 3,3,5,5-tetramelhyl-A-9-octalonc-2.hnving the formula v 1 4. The process which comprises cyclizing ageranyl propionitrile by subjecting it to a strong mineral acid toproduce a substance selected from the group consisting of3,5,5-trimethylA -octalone-2 and 3,5,5-trimethyl-' A -octalone-2 havingrespectively the formulae CH3 CH3 8 References Cited by the Examiner vUNITED STATES PATENTS 2,912,462 11/1959 Goldstein et a1 260-586 OTHERREFERENCES Arrnour et al.. Helv. Chim. Acta, vol. 42, pp. 2233-44(1959).

Augustine: J. Org. Chem.', vol. 23, pp. 1853-6 (1958).

Elseviers Encyclopedia of Organic Chemistry, edited by F. Radt., SeriesIII, vol. 128,- pp.25734 1950).

Robinson et a1.: J. Chem. 'Soc. (London), 1941, pages 386-91 (page 388relied upon).

LEON ZITVER, Primary Examiner.

LORRAINE A. WEINBERGER, DANIEL D. HOR- WITZ, Assistant Examiners.

' and

1. THE PROCESS WHICH COMPRISES CYCLIZING THE COMPOUND